The conventional process for manufacturing and packaging parenteral biopharmaceuticals involves the formulation of a bulk solution in accordance with the measured biological activity of the intermediate material used to formulate the bulk solution. In many cases, particularly at the end of the process, the bulk solution is frozen and stored for making the assay. For this purpose the frozen solution may be stored for several days or even for several weeks. For the subsequent filling of the final packages, such as vials, for e.g. distribution to the end users, the frozen intermediate solution is typically thawed, bulked and loaded into e.g. vials, and then freeze-dried within the vials.
The amount of thawed bulk solution that is loaded into the final packaging e.g. vials, is calculated on the basis of the assay of the intermediate solution. This calculation usually incorporates a large safety margin because of (1) large variation of biological assay and (2) loss of yield in the subsequent sterile fill and freeze-drying process. The loss of yield is due to product stress during this first freezing, storing and thawing step and the following second filling, freezing and drying process. This calculation is of course very difficult and based on product dependent empirical knowledge of the complete process.
In accordance with the heretofore known processes (as shown in FIG. 1), the active agent solution is assayed after the final purification step and then frozen in identified individual lots—consisting of several bags—and stored or shipped for subsequent use. The frozen formulation is then thawed, bulked and then filtered and transferred to bulk containers. The bulk containers are then positioned in a production line, and the liquid product in the bulk containers is then loaded into e.g. individual vials, in the calculated amounts. Prior to filling, the vials are usually washed and sterilized. The loaded (i.e., filled) vials are then arranged on a transfer table, loaded into a freeze-dryer, frozen in an appropriate freezing process, dried in an appropriate drying process, unloaded from the drying process into a transfer table and transferred to a capping line where they are sealed.
The conventional process is an addition of singular processes and technologies which are described in several patents and publications. Novel literature like “Freeze Drying” by G. W. Oetjen, Wiley-VCH, 1999, pages 127-195 describes very accurate and detailed the current state of the art. There are additionally several patents which describe these singular technologies.
U.S. Pat. No. 2,441,730 describes a shell freezer and a dryer which dries the product from the frozen state. In a shell freezer the product is frozen on the inside walls of an axial rotating vial. U.S. Pat. No. 3,281,954 describes a freeze dryer for bulk material which is filled into trays as a solution. These trays are arranged on temperature controlled shelfs and frozen at low temperatures. Than the frozen product is freeze dried and unloaded into a container.
U.S. Pat. No. 3,397,462 describes an apparatus for lyophilization of substances containing an aqueous phase. This patent describes a hermetic sealable cell loader which contains the containers, vials or ampoules filled with sterile solution. This cell loader can be used for prefreezing and subsequent sterile transport of the frozen product into the freeze dryer.
EP 429348 describes a small bottle loading apparatus such as for freezedrying plant. Bottles are collected and stocked on a vibrating table, with a device moving them on to the vibrating table tray. This is a claimed method for transferring filled containers with a loading device into the freeze dryer.
EP 219520 describes an industrial, mechanical handling truck for transferring flat plates or trays on to the horizontal shelves of a processing chamber, e.g. a freeze-drying chamber.
A block diagram of a typical prior art process is shown in FIG. 1. As is shown, the freeze-drying process is usually performed in standard freeze drying chambers which do not have temperature controlled walls. These dryers, unfortunately, provide non homogeneous heat transfer to the vials placed in the dryer chamber. Especially, those vials which are positioned at the edges exchange energy more intensively than those positioned in the center of the plates, due to radiant heat exchange and natural convection in the gap between the wall of the chamber and the stack of plates/shelves. This non-uniformity of energy distribution leads to a variation of freezing and drying kinetics between the vials at the edges and those in the center, and could result in variation in the activities of the active contents of the respective vials. To ensure the uniformity of the final product, it is necessary to conduct extensive development and validation work both at laboratory and production scales.
Therefore there has been a long felt need for a process which avoids the above mentioned disadvantages. The present process fulfills that need.